Method for treatment of gastrointestinal disorders

ABSTRACT

A method for the treatment of gastrointestinal disorders in a patient which comprises administering to the patient a gastric anti-secretory effective amount of a 2-amino-5-hydroxy-4-methylpyrimidine or a substituted amino derivative thereof, optionally in admixture with an additional gastric anti-secretory agent.

This is a division of application Ser. No. 538,233, filed on Oct. 3,1983, now U.S. Pat. No. 4,554,276.

BACKGROUND OF THE INVENTION

This invention relates to novel hydroxy-pyrimidine derivatives, moreparticularly to 2-amino and substitutedamino-5-hydroxy-4-methylpyrimidines. This invention is also concernedwith a process for the preparation of such novel compounds and withpharmaceutical compositions containing the novel compounds as activeingredients.

United Kingdom Patent Application No. 2045756, published Nov. 5, 1980,discloses 2-isopropylamino-5-hydroxy-pyrimidine as an agent for thetreatment of muscular dystrophy. There is no disclosure in this priorapplication of any 4-methyl analogs.

Chronic gastric and duodenal ulcers, together known as peptic ulcers,are the subject of a variety of treatments, including special diets,drug therapy and surgery, depending upon the severity of the condition.Particularly valuable therapeutic agents useful for the treatment ofgastric hyperacidity and peptic ulcers are the histamine-H₂ receptorantagonists, which block the action of the physiologically-activecompound histamine at the H₂ -receptor sites in the animal body andthereby inhibit the secretion of gastric acid.

Copending Patent Application Ser. No. 376486 discloses certain2-guanidino-4-(2-substituted amino-4-imidazolyl)thiazole derivatives ascytoprotective H₂ -antagonists which inhibit ethanol-induced ulcers inrats and thereby have clinical value in the inhibition of gastriculcers. The cytoprotective H₂ -antagonists or application No. 376486 areprepared from intermediate 2-amino-5-acetylimidazoles and these keyintermediates are prepared from 2-amino-5-acetyl oxazole by arearrangement reaction which is disclosed in application No. 376486.

The 5-hydroxypyrimidine derivatives of the present invention, which arenot described per se in application No. 376486, are minor products ofthe aforesaid rearrangement reaction and the preparation thereof isdescribed in more detail hereinafter.

It has now been found that the novel 5-hydroxypyrimidine derivativesproduced as by-products in the general reaction disclosed in applicationNo. 376486, but not isolated or described per se in the disclosure ofthat application, are valuable therapeutic agents.

SUMMARY OF THE INVENTION

Thus, in accordance with the present invention there is provided apharmacologically-active substituted pyrimidine derivative having thegeneral formula: ##STR1## wherein R is hydrogen or (C₁ -C₁₅)alkyl and R'is hydrogen, (C₁ -C₁₅)alkyl, (C₅ -C₈)cycloalkyl, (C₃ -C₁₅) alkenyl,phenyl, (C₄ -C₅)heteroaryl, (C₅ -C₁₇)heteroaralkyl, (C₇ -C₂₀)aralkyl orsubstituted aralkyl wherein the substitutent is halo, (C₁ -C₃)alkyl, (C₁-C₃)alkoxy or trifluoromethyl; or R and R' together with the nitrogenatom to which they are attached form a piperidyl group, a substitutedpiperidyl group wherein the substituent is (C₁ -C₁₅)alkyl or (C₇-C₂₀)aralkyl, or a pyrrolidinyl group, or a pharmaceutically-acceptableacid addition salt thereof.

The novel compounds of the invention are inhibitors of leukotrienesynthesis and potent inhibitors of 5-lipoxygenase enzyme (5-LO) in vitrowhich makes them valuable agents in the treatment of asthma,inflammation, cardiovascular spasm, psoriasis and cancer. Furthermorethe compounds are "cytoprotective", i.e. they inhibit ethanol-inducedulcer formation in rats and thus they are of interest asnon-antisecretory anti-ulcer agents.

Preferred compounds of the invention are2-amino-5-hydroxy-4-methylpyrimidine derivatives of formula (I) whereinR is hydrogen or methyl and R' is hydrogen, (C₁ -C₁₀)alkyl, cyclopentyl,cyclohexyl, (C₃ -C₈)alkenyl, phenyl, furyl, thienyl, (C₇-C₁₂)phenylalkyl or substituted phenylalkyl wherein the substituent ischloro, (C₁ -C₃)alkyl, methoxy or trifluoromethyl; or R and R' togetherwith the nitrogen atom to which they are attached form a piperidylgroup, a substituted piperidyl group wherein the substituent is (C₇-C₁₂)phenylalkyl, or a pyrrolidinyl group, or apharmaceutically-acceptable acid addition salt thereof.

More preferred compounds are those of formula (I) wherein R is hydrogenor methyl and R¹ is (C₆ -C₁₀) alkyl, cyclopentyl, cyclohexyl, (C₆ -C₈)alkenyl, phenyl, (C₇ -C₁₂) phenylalkyl or substituted phenylalkylwherein the substituent is chloro, (C₁ -C₃)alkyl, methoxy ortrifluoromethyl; or R and R' together with the nitrogen atom to whichthey are attached form a piperidyl group, a substituted piperidyl groupwherein the substituent is (C₇ -C₁₂)phenylalkyl, or a pyrrolidinylgroup, or a pharmaceutically-acceptable acid addition salt thereof.

Particularly preferred compounds are the following:

The compound of formula (I) wherein R is hydrogen and R' is (CH₂)₆ C₆H₅, i.e. 2-[N-(6-phenylhexylamino)]-5-hydroxy-4-methylpyrimidine, or thehydrochloride salt thereof;

The compound of formula (I) wherein R is hydrogen and R' is (CH₂)₄ C₆H₅, i.e. 2-[N-(4-phenylbutylamino)]-5-hydroxy-4-methylpyrimidine, or thehydrochloride salt thereof; and

The compound of formula (I) wherein R and R' together with the nitrogenatom to which they are attached form the group of the formula: ##STR2##i.e. 2-[4-(3-phenylpropyl)-N-piperidino]-5-hydroxy-4-methylpyrimidine orthe hydrochloride salt thereof.

The present invention also provides a novel process for the preparationof a compound having the general formula: ##STR3## wherein R is hydrogenor (C₁ -C₁₅)alkyl and R' is hydrogen, (C₁ -C₁₅)alkyl, (C₅-C₈)cycloalkyl, (C₃ -C₁₅) alkenyl, phenyl, (C₄ -C₅)heteroaryl, (C₅-C₁₇)heteroaralkyl, (C₇ -C₂₀)aralkyl or substituted aralkyl wherein thesubstituent is halo, (C₁ -C₃)alkyl, (C₁ -C₃)alkoxy or trifluoromethyl;or R and R' together with the nitrogen atom to which they are attachedform a piperidyl group, a substituted piperidyl group wherein thesubstituent is (C₁ -C₁₅)alkyl or (C₇ -C₂₀)aralkyl, or a pyrrolidinylgroup, or an acid addition salt thereof in substantially pure form;which comprises reacting 5-acetyl-2-aminooxazole of the formula:##STR4## with an amine of the formula RR'NH in the presence of water ata temperature within the range of 90° to 125° C., and isolating thedesired compound of formula (I) from the resulting product mixture, and,if desired, converting the compound into a pharmaceutically-acceptableacid addition salt by reaction with an appropriate acid.

The 5-acetyl-2-aminooxazole of formula (II) above is a known compound.Kochetikov et al., Chemical Abstracts 54: 14230h (1960). A preferredmethod for the preparation thereof is disclosed in application No.376486 and is repeated hereinafter.

The amines used in the preparation of the compounds according to theinvention are generally commercially available or may be prepared bystandard methods. A specific method for the preparation of6-phenylhexylamine which is the starting amine for a particularlypreferred compound of the invention is particularly describedhereinafter.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of the compounds of formula (I) may be illustrated bythe following reaction scheme: ##STR5##

The general procedure for carrying out the above process comprisesheating a mixture of 5-acetyl-2-aminooxazole (formula II); 3-6equivalents of the appropriate amine of formula RR'NH and water at atemperature of 90° to 125° C. (external) until all the oxazole isconsumed, as monitored by t.l.c. (2-96 hours). The mixture is thenconcentrated, distilled if necessary to remove the excess amine, and theresidue chromatographed over silica gel using 4:1 ethyl acetate/hexaneas eluent. The desired pyrimidine of formula (I) is eluted first andrecrystallized from an appropriate solvent. The preferred solvent forspecific compounds according to the invention is given in the Examples.

If desired, the imidazole of formula (III) then may be eluted from thecolumn using 19:1 chloroform/methanol as eluent. As stated above, the2-amino-5-acetylimidazole of formula (III) is a key intermediate in thepreparation of the cytoprotective thiazole derivatives disclosed inapplication No. 376486.

Where the pyrimidine product of formula (I) is an oil it is converted tothe hydrochloride salt by dissolving in alcohol, adding hydrochloricacid gas to saturation, evaporating the alcohol followed by triturationof the residue with ether.

The novel compounds of formula (I) are useful as inhibitors oflipoxygenase synthesis and as cytoprotective agents for the treatment ofvarious pulmonary, gastrointestinal, inflammatory, dermatological andcardiovascular conditions, as well as cancer. In particular, thecompounds have utility, both as the sole active agent and also incombination with other active agents, for the treatment of asthma,bronchitis, peptic ulcers, psoriasis, arthritis, inflammatory boweldisease or cardiovascular spasm, such as acute myocardial infarctions.

Accordingly the present invention further provides a pharmaceuticalcomposition comprising a pharmaceutically-effective amount of a compoundof formula (I) or a pharmaceutically-acceptable acid addition saltthereof in admixture with a pharmaceutically-acceptable diluent orcarrier.

The pharmaceutical composition according to the invention may alsoinclude a standard non-steroidal anti-inflammatory agent or anadditional gastric anti-secretory agent.

It has been found that the use of the compounds of this inventiontogether with the aforesaid active agents is particularly beneficial.Without wishing to be bound by any theory, it would appear that thebeneficial effect produced by the co-administration of the compounds ofthe invention with other active agents as herein defined arises eitherfrom a synergistic or additive action of the two active agents or fromthe fact that the compounds of this invention have a tendency tosuppress deleterious side-effects which may arise when the other agentsare used alone, such as the gastric irritation caused by non-steroidalanti-inflammatory agents.

The invention still further provides a method for the treatment ofasthma, bronchitis, peptic ulcers, psoriasis, arthritis, inflammatorybowel disease or acute myocardial infarctions in a patient, whichcomprises administering to the patient a pharmaceutically-effectiveamount of a compound of formula (I) or a pharmaceutically-acceptableacid addition salt thereof.

In accordance with the preferred embodiments described above, theinvention yet further provides a method for the treatment of arthritisand inflammation conditions in a patient, which comprises co-admisteringto the patient a pharmaceutically-effective amount of a compound offormula (I) or a pharmaceutically-acceptable acid addition salt thereofand a standard non-steroidal anti-inflammatory agent.

The invention also provides a method for the treatment of peptic ulcersand other gastrointestinal disorders in a patient, which comprisesco-administering to the patient a pharmaceutically-effective amount of acompound of formula (I) or a pharmaceutically-acceptable acid additionsalt thereof and an additional gastric anti-secretory agent.

Preferred anti-inflammatory agents used in the above embodiments of theinvention are:

aspirin;

1-(p-chorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid, known asindomethacin and described in U.S. Pat. No. 3,161,654, now expired;

(+)-6-methoxy-α-methyl-2-naphthaleneacetic acid, known as naproxen anddescribed in U.S. Pat. No. 3,641,161;

2-[(2,6-dichlorophenyl)amino]-benzene acetic acid, monosodium salt,known as diclofenac;

α-methyl-4-(2-methylpropyl)-benzene acetic acid, known as ibuprofen anddescribed in U.S. Pat. No. 3,385,886; and

4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide1,1-dioxide, known as piroxicam and described in U.S. Pat. No.3,591,584.

Preferred gastric anti-secretory agents which may be co-administeredwith the compounds of this invention include:

2-cyano-1-methyl-3-[2-{[(5-methylimidazol-4-yl)methyl]thio}ethyl]guanidine, known as cimetidine and described in U.S.Pat. No. 3,950,333;

N-[2-{[5-[(dimethylamino)methyl]furfuryl]thio}ethyl]-N'-methyl-2-nitro-1,1-ethenediamine, known as ranitidine;

3-[[[2-(diaminomethylene)amino]-4-thiazolyl]methylthio]-N-2-sulfamoylpropionamidine,known as famotidine;

2-cyano-1-[2-[[(5-methylimidazol-4-yl)methyl]thio]ethyl]-3-(2-propynyl)guanidinemonohydrochloride, known as etintidine;

5-amino-1-methyl-1H-1,2,4-triazol-5-yl[3-(α-piperidino-m-tolyloxy)-propyl]amine,known as lamtidine; and

2-guanidino-4-(2-methyl-4-imidazolyl) thiazole and the hydrohalide saltsthereof, particularly the hydrobromide, as described in U.S. Pat. No.4,374,843.

For treatment of the various conditions described above the compounds ofthe invention may be administered to a subject in need of treatment,either alone or in combination with the other described active agents,by a variety of conventional routes of administration, including oral,parenteral and topical.

In general, a therapeutically-effective dose for the active compounds ofthe invention will range from 1 to 100 mg/kg. body weight of the subjectto be treated per day, with a preferred dose of 1 to 20/mg/kg. per day.

When used in combination with other active agents, as described above,the active compound of the invention will be co-administered with atherapeutically-effective dose of the other active agent. For example,in the treatment of inflammation a therapeutically-effective daily doseof a compound of the invention would be co-administered with 20 mg. ofpiroxicam.

As another example, for the treatment of peptic ulcers, atherapeutically-effective dose of a compound of the invention would beco-administered with 300 mg. of cimetidine four times a day.

Variations in dosage will necessarily occur depending upon the conditionof the subject and the physician responsible for administration willdetermine the appropriate dose for the individual subject.

The following Preparations illustrate the preparation of startingcompounds used in the preparation of the compounds according to theinvention. The subsequent Examples illustrate the preparation ofcompounds of formula (I) according to the process of the invention.

PREPARATION A Preparation of 5-Acetyl-2-Aminooxazole (Formula (II))

A mixture of 132.3 g (0.80 mole) of 2-bromo-1-hydroxy-3-oxo-1-butene,120.1 g (2.0 mole) of urea, and 1.85 l of acetone was heated at refluxwith overhead stirring for one hour. The mixture was concentrated andthe oil residue was taken up into 600 ml of water, then made basic withconcentrated ammonium hydroxide. After sitting at room temperature for0.5 hour, a precipitate formed. This was collected, and dried in vacuoto give 61.1 g of crude product. The filtrate was again concentrated andthe oil residue taken up in 50 ml of water and again made basic withconcentrated ammonium hydroxide. After sitting overnight a second cropof crude product, amounting to 17.6 g was isolated. Both crops werecombined and recrystallized from methanol to give 50.3 g (50%) of5-acetyl-2-amino-oxazole, m.p. 214°-215° C.

PREPARATION B Preparation of 6-Phenylhexylamine

a. 6-Phenylcapronitrile. A solution of 50.0 g (0.284 mole) of6-bromocapronitrile in 550 ml of benzene was cooled to 5° C. and to thiswas added 77.3 g (0.580 mole) of anhydrous aluminum chloride in portionsover a 10 minute period. The ice bath was removed and the vigorouslystirred mixture was warmed slowly to reflux. After 2 hours at reflux,the mixture was cooled to room temperature, then poured slowly into amixture of 50 ml of concentrated hydrochloric acid and 250 ml of icewater. The layers were separated and the aqueous portion was extractedtwice with 125 ml portions of ether. The combined organic extracts werewashed with 100 ml of saturated sodium bicarbonate solution, 100 ml ofsaturated sodium chloride solution, then dried over sodium sulfate,filtered, and evaporated leaving 53 g of a crude red/brown oil.Distillation under reduced pressure afforded 42.4 g (86%) of the nitrileas a pale yellow oil, bp 136°-140 ° C./2.5 mm of Hg.

b. 6-Phenylhexylamine. A mixture of 42.4 g (0.245 mole) of6-phenylcapronitrile, 3 g of Raney nickel, 200 ml of ethanol, and 30 mlof concentrated ammonium hydroxide was hydrogenated at 43 psi, and roomtemperature for 24 hours. The catalyst was removed by filtration and thefiltrate concentrated leaving an oil. Distillation under reducedpressure afforded 32.8 g (75.6%) of 6-phenylhexylamine as a colorlessoil, bp 118°-123° C./1.5 mm of Hg. NMR (CDCl₃): 7.20 (s, 5H); 2.80-2.55(m, 4H); 1.80-1.10 (m, 8H); 1.00 (s, 2H - exchangeable with D₂ O).

Analogous phenyl alkylamines may prepared in a similar manner to thatillustrated in Preparation B using the appropriate starting nitriles.

PREPARATION C Preparation of 6-(p-chlorophenyl)hexylamine. ##STR6##6-(p-Chlorophenyl)hex-5-enoic acid (IV).

A solution of sodium dimsylate (prepared from 12.5 g of 50% sodiumhydride and dry DMSO) was stirred at 30°-35° C. and 39.1 g (0.088 mole)of 5-triphenylphosphonium pentanoic acid bromide was added in portions.The resulting dark red solution was stirred at room temperature for 10minutes, then a solution of 10.0 g (0.068 mole) of p-chlorobenzaldehydein 20 ml of dry DMSO was added dropwise over 10 minutes (cooling wasnecessary to maintain 30°-35° C. temperature). The mixture was stirredat room temperature for 18 hours, then poured into 300 ml of water andacidified to pH 2 with 6N hydrochloric acid. The mixture was extractedtwice with 500 ml portions of ethyl acetate. The combined ethyl acetateportions were extracted three times with 35 ml portions of sodiumhydroxide. The combined sodium hydroxide extracts were brought to pH 3with 6N hydrochloric acid, then reextracted with ethyl acetate. Thecombined ethyl acetate extracts were dried over magnesium sulfate,filtered, and evaporated leaving a semi-solid that was chromatographedover silica gel using 19:1 methylene chloride/methanol as eluent. Theproduct, isolated in quantitative yield was contaminated withtriphenyl-phosphine oxide, but was of sufficient purity to utilize inthe next step.

6-(pChlorophenyl)hexanoic acid (V).

A mixture of 49.3 g (0.219 mole) of 6-(p-chlorophenyl)hex-5-enoic acid,3.0 g of 10% Pd/C, and 300 ml of ethyl acetate was hydrogenated at 45psi and room temperature for 20 hours. The catalyst was removed byfiltration through a Celite pad, and the filtrate concentrated to give21.3 g (43%) of V as an oil, which was used without furtherpurification.

6-(p-Chlorophenyl)hexanamide (VI).

A mixture of 21.3 g (0.094 mole) of 6-(p-chlorophenyl)hexanoic acid (V)and 95 ml of thionyl chloride was heated at reflux for 3 hours. Themixture was cooled, then concentrated. The residue was dissolved in 45ml of ether and this solution was slowly added to 67 ml of concentratedammonium hydroxide at 5° C. After addition, the mixture was vigorouslystirred at 5° C. for one hour, then diluted with 100 ml of water andextracted with ether. The combined ether extracts were dried (magnesiumsulfate) filtered, and evaporated leaving 16.4 g (77%) of VI as a tansolid mp. 87°-89° C.

6-(p-Chlorophenyl)hexylamine (VII).

A solution of 16.4 g (0.073 mole) of 6-(p-chlorophenyl hexanamide (VI)in 30 ml. of dry tetrahydrofuran was added dropwise to a stirredsolution of 170 ml of 1.0M diborane/tetrahydrofuran solution (Aldrich)at 0° C. under a nitrogen atmosphere. After addition, the mixture wasstirred at 0° C. for 15 minutes, then warmed to reflux and kept therefor 2.5 hours. The mixture was cooled to room temperature, and 85 ml of6N hydrochloric acid was added cautiously to quench the reaction. Thesolvent was removed and the aqueous mixture was brought to pH 10 with10% sodium hydroxide solution. The aqueous mixture was extracted threetimes with 60 ml portions of ethyl acetate. The combined ethyl acetateextracts were washed with saturated sodium chloride solution, dried oversodium sulfate, filtered, and evaporated leaving an oil. Distillationunder reduced pressure afforded 10.4 g (67%) of VII as a colorless oil,bp. 108°-115° C. (0.3 torr).

Analogous substituted phenyl alkenylamines may be prepared in a similarmanner to that illustrated in Preparation C using the appropriatestarting alkanoic acid derivatives.

EXAMPLE 1 2-[N-(6-Phenylhexylamino)]-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=C₆ H₅ (CH₂)₆ ]

A mixture of 3.0 g (0.024 mole) of 5-acetyl-2-aminooxazole (PreparationA), 15 ml of 6-phenylhexylamine (Preparation B), and 3.3 ml of water washeated at 110° C. for 4.5 hours. The mixture was cooled to roomtemperature, 15 ml of isopropanol was added, and the mixture was allowedto stand at 5° C. for 17 hours. The resulting precipitate, which is2-[N-(6-phenylhexylamino)]-5-acetyl-1H-imidazole, was collected and setaside. Concentration of the filtrate afforded an oil which waschromatographed over silica gel using 1:1 ethyl acetate/hexane aseluent. The less polar material was the desired product which wasinitially isolated as an oil but which solidified on standing.Recrystallization from 4:1 hexane/toluene afforded 811 mg (12%) of thetitle compound as a tan crystalline solid, mp 72°-74° C.

Analysis: CALC. C, 71.55; H, 8.12; N, 14.72. FOUND 71.55; 7.87; 14.66.

EXAMPLE 2 2-[N-(5-Phenylpentylamino)]-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=C₆ H₅ (CH₂)₅ ]

A mixture of 2.5 g (0.020 mole) of 5-acetyl-2-aminooxazole, 15 ml of5-phenylpentylamine, 30 ml of water, and 20 ml of isopropanol, washeated at reflux for 24 hours. The mixture was cooled with an ice bathand the resulting precipitate, which was2-[N-(5-phenylpentylamino)]-5-acetyl-1H-imidazole, was collected and setaside. The filtrate was concentrated and the oil residue was distilledunder high vacuum to remove the excess amine. The dark residue was thenchromatographed over silica gel using 9:1 ethyl acetate/hexane aseluent. The less polar material was the desired product which wasisolated as an oil initially. Trituration of this oil with 1:1toluene/cyclohexane gave 346 mg (6%) of the title compound as a whitecrystalline solid, mp 80°-82° C.

Analysis: CALC. C, 70.82; H, 7.99; N, 15.49. FOUND 70.59; 7.79; 15.49.

EXAMPLE 3 2-[N-(4-Phenylbutylamino)]-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=C₆ H₅ (CH₂)₄ ]

A mixture of 2.5 g (0.020 mole) of 5-acetyl-2-aminooxazole, 15 ml of4-phenylbutylamine, 30 ml of water, and 20 ml of isopropyl alcohol, washeated at reflux for 22.5 hours. The mixture was cooled and the alcoholwas removed under reduced pressure. The precipitate, which was a2-[N-(4-phenylbutylamino)]-5-acetyl-1H-imidazole, was collected and setaside. The filtrate was concentrated and the residue was chromatographedover silica gel using 4:1 ethyl acetate/hexane as eluent. The less polarmaterial was the desired product which was initially isolated as an oil,but which solidified when triturated with hexane to give 445 mg (9%) ofthe title compound as a white crystalline solid, mp 101°-104° C.

Analysis: CALC. C, 70.01; H, 7.44; N, 16.33. FOUND 69.75; 7.37; 16.14.

EXAMPLE 4 2-[N-(3-Phenylpropylamino)]-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=C₆ H₅ (CH₂)₃ ]

A mixture of 2.5 g (0.020 mole) of 5-acetyl-2-aminooxazole, 20 ml of3-phenylpropylamine, 30 ml of water and 10 ml of isopropyl alcohol washeated at 130° (external) for 9 hours. The mixture was concentrated, andthe residue distilled under reduced pressure to remove the excess amine.Trituration of the residue with acetonitrile afforded a precipitate,which was 2-N-(3-phenylpropylamino)]-5-acetyl-1H-imidazole, and whichwas collected and set aside. Concentration of the filtrate, left an oilwhich was chromatographed over silica gel using 4:1 ethyl acetate/hexaneas eluent. The less polar material was the desired product, and it wasisolated as a solid. Recrystallization from cyclohexane afforded 0.46 g(10%) of the title compound as a white solid, mp 101°-103° C.

Analysis: CALC. C, 69.11; H, 7.04; N, 17.27. FOUND 68.89; 6.72; 16.94.

EXAMPLE 52-[N-(3-(p-Chlorophenyl)propylamino)]-5-hydroxy-4-methylpyrimidine

Formula I: R=H; R'=pCl-C₆ H₄ (CH₂)₃ ]

A mixture of 2.5 g (0.02 mole) of 5-acetyl-2-aminooxazole, 10.5 g (0.062mole) of 3-(p-chlorophenyl)propylamine, and 2.7 ml of water was heatedat 110° C. (external) for 16 hours. The mixture was allowed to cool toroom temperature and diluted with 15 ml of water. The resultingprecipitate, which is2-[N-(3-(p-chlorophenyl)propylamino)]-5-acetyl-1H-imidazole, wascollected and set aside. Concentration of the filtrate afforded as oilwhich was chromatographed over silica gel using 1:1 ethyl acetate/hexaneas eluent. The less polar material was the desired product which wasisolated as a solid. Recrystallization from acetonitrile afforded 0.71 g(13%) of the title compound, mp 99°-100° C.

Analysis: CALC. C, 60.54; H, 5.81; N, 15.13. FOUND 60.17; 5.74; 14.85.

EXAMPLE 62-[N-(5-(p-Chlorophenyl)pentylamino)]-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=pCl-C₆ H₄ (CH₂)₅ ]

A mixture of 1.00 g (0.008 mole) of 5-acetyl-2-aminooxazole, 3.35 g(0.017 mole) of 5-(p-chlorophenyl)pentylamine, and 1.5 ml of water washeated at 110° C. (external) for 20 hours. The mixture was cooled, thendiluted with 7 ml of isopropanol. The resulting precipitate, which is2-[N-5-(p-chlorophenyl)pentylamino)]-5-acetyl-1H-imidazole, wascollected and set aside. Concentration of the filtrate afforded an oilwhich was chromatographed over silica gel using 1:1 ethyl acetate/hexaneas eluent. The less polar material was the desired product and wasisolated as a solid. Recrystallization from 4:1 ethyl acetate/hexanegave 0.59 g (24%) of the title compound as a crystalline solid, mp69°-71° C.

Analysis: CALC. C, 62.84; H, 6.59; N, 13.79. FOUND 63.16; 6.59; 13.79.

EXAMPLE 7 2-Amino-5-hydroxy-4-methylpyrimidine

Formula I: R=H; R'=H]

A mixture of 10 g (0.079 mole) of 5-acetyl-2-aminooxazole, and 200 ml ofconc. ammonium hydroxide was placed in a 500 ml three-neckedround-bottomed flask fitted with a condenser and gas inlet tube. Themixture was heated at reflux and ammonia gas was bubbled into themixture for 30 hours. The mixture was concentrated and the solid residuewas taken up into ethanol and chromatographed over silica gel using 9:1chloroform/methanol as eluent. The less polar material was the desiredproduct and was isolated as a solid. Recrystallization from acetonitrileafforded 2.3 g (22%) of a crystalline solid, mp 202.5°-204° C.

Analysis: CALC. C, 47.99; H, 5.64; N, 33.50. FOUND 48.15; 5.64; 33.26

EXAMPLE 8 2-(N-Hexylamino)-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=CH₃ (CH₂)₅ ]

A mixture of 8.0 g (0.63 mole) of 5-acetyl-2-aminooxazole, 44 ml ofhexylamine, and 11 ml of water was heated at 140° C. (external) for 1.5hours. The mixture was cooled to room temperature and diluted with 53 mlof water. The resulting precipitate, which is2-N-hexylamino-5-acetyl-1H-imidazole, was collected and set aside.Concentration of the filtration left a dark oil which waschromatographed over silica gel using 9:1 ethyl acetate/hexane aseluent. The less polar material was the desired product which amountedto 2.02 g (20%) of a tan crystalline solid, mp 90°-91° C.

Analysis: CALC. C, 63.13; H, 9.15; N, 20.08. FOUND 63.02; 9.06; 20.09.

EXAMPLE 9 2-(N-Octylamino)-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=CH₃ (CH₂)₇ ]

A mixture of 3.2 g (0.025 mole) of 5-acetyl-2-aminooxazole, 20 ml ofoctylamine, 40 ml of water, and 35 ml of isopropanol was heated at 110°C. (external) for 22 hours. The mixture was cooled and the resultingprecipitate, which is 2-N-octylamino-5-acetyl-1H-imidazole was collectedand set aside. Concentration of the filtrate left a dark oil which waschromatographed over silica gel using 4:1 ethyl acetate/hexane aseluent. The less polar material was the desired product which amountedto 302 mg of analytically pure white solid, mp 84.5°-87° C.

Analysis: CALC. C, 65.78; H, 9.77; N, 17.70. FOUND 65.39; 9.65; 17.65.

EXAMPLE 102-[N-(6-p-chlorophenyl)hexylamino]-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=pClC₆ H₄ (CH₂)₆ ]

A mixture of 2.5 g (0.020 mole) of 5-acetylaminooxazole, 10.4 g (0.049mole) of 6-(p-chlorophenyl)hexylamine, and 3.5 ml of water was heated at110° C. (external) for 20 hours. The mixture was concentrated to removethe water, and then chromatographed over silica gel using 1:1 ethylacetate/hexane as eluent. The less polar material was the desiredproduct and was isolated as a solid. Recrystallization from 4:1 ethylacetate/hexane afforded 0.65 g (11%) of the title compound, mp 69°-72°C.

Analysis: CALC. C, 63.84; H, 6.93; N, 13.14. FOUND 64.06; 6.90; 12.87.

EXAMPLE 11 2-(4-Benzyl-N-piperidino)-5-hydroxy-4-methlpyrimidine##STR7##

A mixture of 3.5 G (0.030 mole) of 5-acetyl-2-aminooxazole, 20 ml of4-benzylpiperidine, and 5.2 ml of water was heated at reflux for 20hours. The mixture was cooled to room temperature and diluted with 30 mlof water. The organic layer was separated and chromatographed oversilica gel using 1:1 ethyl acetate/hexane as eluent. The less polarmaterial was the desired product and was isolated as a solid.Recrystallization from toluene gave 0.77 g (10%) of the title product,mp 126°-128° C.

Analysis: CALC. C, 72.06; H, 7.47; N, 14.83. FOUND 72.23; 7.62; 14.82.

EXAMPLE 122-[4-(3-Phenylpropyl)-N-piperidino]-5-hydroxy-4-methylpyrimidinehydrochloride ##STR8##

A mixture of 3.5 g (0.030 mole) of 5-acetyl-2-aminooxazole, 20 ml of4-(3-phenylpropyl)piperidine, and 5.2 ml of water was heated at refluxfor 20 hours. The mixture was cooled to room temperature and dilutedwith 30 ml of water. The organic layer was separated and chromatographedover silica gel using 1:1 ethyl acetate/hexane as eluent. The less polarmaterial was the desired product and was isolated as an oil. This wasconverted to its hydrochloride by dissolving in 30 ml of ethanol,saturating this solution with hydrochloric acid gas, concentration ofthis hydrochloride solution to 5 ml and trituration with ether. In thisway, 2.9 g (30%) of the hydrochloride salt of the title compound wasisolated as an off-white solid, mp 149°-151° C.

Analysis: CALC. C, 65.60; H, 7.53, N, 12.08. FOUND 65.41; 7.50; 11.85.

EXAMPLE 13 2-N,N-Dimethylamino-5-hydroxy-4-methylpyrimidine

[Formula I: R=CH₃ ; R'=CH₃ ]

A mixture of 12 g (0.095 mole) of 5-acetyl-2-aminooxazole, and 350 ml of40% dimethylamine in water was stirred at room temperature for 7 hours.The mixture was concentrated and the residue chromatographed over silicagel using 4:1 ethyl acetate/hexane as eluent. The less polar materialwas the desired product and was isolated as a solid. Recrystallizationfrom cyclohexane afforded 6.4 g (44%) of the title compound as a whitecrystalline solid, mp 114°-116° C.

Analysis: CALC. C, 54.89; H, 7.24; N, 27.43. FOUND 54.91; 7.20 27.27.

EXAMPLE 14 2-(N-n-Nonylamino)-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=CH₃ (CH₂)₈ ]

A mixture of 2.5 g (0.020 mole) of 5-acetyl-2-aminooxazole, 15 ml ofn-nonylamine, 30 ml of water, and 25 ml of isopropanol was heated atreflux for 20 hours. The mixture was cooled, then distilled underreduced pressure to remove the excess n-nonylamine. The residue waschromatographed over silica gel using 7:2 ethyl acetate/hexane aseluent. The less polar material was the desired product, which amountedto 0.55 g of a brown solid. Recrystallization with hexane afforded 0.36g (7%) of the title compound as a crystalline solid, mp 78°-81° C.

Analysis: Calculated for C₁₄ H₂₅ N₃ O: CALC. C, 66.89; H, 10.02; N,16.72. FOUND: 66.50 9.63; 16.66.

EXAMPLE 15 2-(N-2-Octylamino)-5-hydroxy-4-methylpyrimidine hydrochloride##STR9##

A mixture of 4.0 g (0.032 mole) of 5-acetyl-2-aminooxazole, 21.6 ml of2-octylamine, and 5.6 ml of water was heated at reflux for 17.5 hours.The mixture was cooled, then distilled under reduced pressure to removethe excess 2-octylamine. The residue was chromatographed over silica gelusing 9:1 ethyl acetate/hexane as eluent. The less polar material wasthe desired product which was isolated as a dark oil. This was taken upin methanol, saturated with hydrochloric acid gas, then concentrated.The residue was triturated with ether to give 1.56 g (13%) of theproduct as it hydrochloride salt, mp 118°-121° C.

Analysis: Calculated for C₁₃ H₂₂ N₃ O. HCl. 1/2H₂ O: CALC. C, 55.20; H,8.91; N, 14.86. FOUND: 55.71; 8.90; 14.86.

EXAMPLE 16 2-(N-n-Decylamino)-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=CH₃ (CH₂)₉ ]

A mixture of 2.5 g (0.020 mole) of 5-acetyl-2-aminooxazole, 15 ml ofn-decylamine, 30 ml of water, and 30 ml of isopropanol was heated atreflux for 20 hours. The mixture was cooled and the resultingprecipitate, which is 2-n-decylamino-5-acetylimidazole, was set aside.The filtrate was concentrated and the oil residue was chromatographedover silica gel using 7:2 ethyl acetate/hexane as eluent. The less polarmaterial was the desired product and this amounted to an 0.50 g of agum. Crystallization with hexane gave 0.35 g (11%) of the title compoundas a white solid, mp 82°-83° C.

Analysis: Calculated for C₁₅ H₂₇ N₃ O: CALC: C, 67.88; H, 10.25; N,15.83. FOUND: 67.49; 9.98; 15.77.

EXAMPLE 17 2-(N-Phenylamino)-5-hydroxy-4-methylpyrimidine

[Formula I: R=H; R'=C₆ H₅ ]

A mixture of 2.5 g (0.020 mole) of 5-acetyl-2-aminooxazole, 15 ml ofaniline, 30 ml of water, and 15 ml of isopropanol was heated at refluxfor 91 hours. The mixture was cooled, and the isopropanol was removedunder reduced pressure. The resulting yellow solid precipitate, whichproved to be a mixture of 5-acetyl-2-aminooxazole and2-N-phenylamino-5-acetylimidazole, was separated and set aside. Thefiltrate was concentrated under reduced pressure to remove the water andexcess amine, and the residue chromatographed over silica gel using 2:1hexane/ethyl aceate as eluent. The less polar material was the desiredproduct and amounted to a brown solid. Recrystallization fromacetonitrile afforded 0.18 g (4.5%) of the title compound, mp 164°-166°C.

Analysis: Calculated for C₁₁ H₁₁ N₃ O: C, 65.66; H, 5.51; N, 20.88.Found: 65.21; 5.58; 20.51.

EXAMPLES 18-23

Following the general procedure described in the preceding Examples, anumber of additional compounds according to the invention were prepared.Physical data and yields for these additional compounds are set out inthe following Table I.

                                      TABLE 1                                     __________________________________________________________________________    Physical data for additional compounds of the formula:                         ##STR10##                                                                                         M.P. °C.                                          Example No.                                                                          R   R'        (recrystallization solvent)                                                                   Yield                                                                              Analytical Data                     __________________________________________________________________________    18     H   CH.sub.2CHCH.sub.2                                                                      122-125 (cyclohexane)                                                                         13%  CALC. C, 58.16;                                                                          H,                                                                                 N, 25.44                                                      FOUND  .sup. 57.97;                                                                       .sup. 6.71;                                                                        .sup. 25.38        19     H   (CH.sub.3).sub.2 CHCH.sub.2 CH.sub.2                                                     95-97 (cyclohexane)                                                                          14%  CALC. C, 61.51;                                                                          H,                                                                                 N, 21.52                                                      FOUND  .sup. 61.14;                                                                       .sup. 8.44;                                                                        .sup. 21.39        20     H                                                                                  ##STR11##                                                                               99-100.5 (pet. ether)                                                                        23%  CALC. FOUND                                                                         C, 59.64; 59.35;                                                                   H,                                                                                 N, 23.18 23.05      21     H   CH.sub.3 CH.sub. 2 CH.sub.2                                                             125-127 (toluene)                                                                             15%  CALC. C, 57.46;                                                                          H,                                                                                 N, 25.13                                                      FOUND  .sup. 57.40;                                                                       .sup. 7.82;                                                                        .sup. 24.67        22     H   Cyclopentyl                                                                             122-124 (cyclohexane)                                                                         12%  CALC. C, 62.15;                                                                          H,                                                                                 N, 21.74                                                      FOUND  .sup. 61.89;                                                                       .sup. 7.60;                                                                        .sup. 21.59        23     H   3-CF.sub.3 C.sub.6 H.sub.4 (CH.sub.2).sub.2                                             163-165 (methanol/diethyl ether)                                                              14%  CALC. AS .1HCl 1.5H.sub.2 O                (Hydrochloride salt)                     C, 46.48;                                                                          H,                                                                                 N, 11.62                                                      FOUND  .sup. 46.89;                                                                       .sup. 4.70;                                                                        .sup. 11.85        24     CH.sub.3                                                                          CH.sub.3 (CH.sub.2).sub.7                                                               124-126.5 (ethanol/diethyl ether)                                                             10%  CALC. AS .1HCl                             (Hydrochloride salt)                     C, 58.42;                                                                          H,                                                                                 N, 14.60                                                      FOUND  .sup. 57.91;                                                                       .sup. 9.15;                                                                        .sup. 14.35        25     CH.sub.3                                                                          CH.sub.3 (CH.sub.2 ).sub.5                                                              124-125 (ethanol/diethyl ether)                                                                7%  CALC. AS .1HCl                             (Hydrochloride salt)                     C, 55.48;                                                                          H,                                                                                 N, 16.18                                                      FOUND  .sup. 54.88                                                                        .sup. 8.37;                                                                        .sup. 15.75        __________________________________________________________________________

I claim:
 1. A method for treatment of gastro-intestinal disorders in apatient, which comprises administering to the patient a gastricanti-secretory effective amount of a substituted pyrimidine having theformula: ##STR12## wherein R is hydrogen or (C₁ -C₁₅)alkyl and R' ishydrogen, (C₁ -C₁₅)alkyl, (C₅ -C₈)cycloalkyl, (C₃ -C₁₅)alkenyl, phenyl,furyl, thienyl, (C₇ -C₂₀)aralkyl or substituted aralkyl wherein thesubstitutent is halo, (C₁ -C₃)alkyl, (C₁ -C₃)alkoxy or trifluoromethyl;or R and R' together with the nitrogen atom to which they are attachedform a piperidyl group, a substituted piperidyl group wherein thesubstituent is (C₁ -C₁₅)alkyl or (C₇ -C₂₀)aralkyl, or a pyrrolidinylgroup, or a pharmaceutically-acceptable acid addition salt thereof.
 2. Amethod for the treatment of peptic ulcers and other gastrointestinaldisorders in a patient, which comprises co-administering to the patienta pharmaceutically-effective amount of a compound according to claim 1and an additional gastric anti-secretory agent.
 3. A method according toclaim 2, wherein the additional gastric anti-secretory agent iscimetidine, ranitidine, famotidine, etintidine, lamtidine or2-guanidino-4-(2-methyl-4-imidazolyl)thiazole or a hydrohalide saltthereof.